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BACKGROUND: Mental health issues among healthcare workers remain a serious problem globally. Recent surveys continue to report high levels of depression, anxiety, burnout and other conditions amongst various occupational groups. Novel approaches are needed to support clinician well-being. OBJECTIVE: This integrative literature review aims to explore the current state of research examining the use of generative artificial intelligence (GenAI) and machine learning (ML) systems to predict mental health issues and identify associated risk factors amongst healthcare professionals. METHODS: A literature search of databases was conducted in Medline then adapted as necessary to Scopus, Web of Science, Google Scholar, PubMed and CINAHL with Full Text. Eleven studies met the inclusion criteria for the review. RESULTS: Nine studies employed various machine learning techniques to predict different mental health outcomes among healthcare workers. Models showed good predictive performance, with AUCs ranging from 0.82 to 0.904 for outcomes such as depression, anxiety and safety perceptions. Key risk factors identified included fatigue, stress, burnout, workload, sleep issues and lack of support. Two studies explored the potential of sensor-based technologies and GenAI analysis of physiological data. None of the included studies focused on the use of GenAI systems specifically for providing mental health support to healthcare workers. CONCLUSION: Preliminary research demonstrates that AI/ML models can effectively predict mental health issues. However, more work is needed to evaluate the real-world integration and impact of these tools, including GenAI systems, in identifying clinician distress and supporting well-being over time. Further research should aim to explore how GenAI may be developed and applied to provide mental health support for healthcare workers.
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OBJECTIVES: To determine the prevalence of Chlamydia trachomatis (CT) in the population screened at sexually transmitted infection (STI) clinics on Reunion Island and to identify risk factors for CT infection. PATIENTS AND METHODS: This cross-sectional multicenter study was conducted in 2017-2018. Data were obtained from self-administered questionnaires and multiplex PCR tests. RESULTS: The overall prevalence of CT in the screened population was 8.6% (95% CI 7.7-9.5%). The prevalence of urogenital CT was highest in women under 18 (13.2%, 95% CI 9.3-18.1%) and in men who have sex with men under 18 (13.3%, 95% CI 1.6-48.2%). Risk factors associated with CT infection in multivariate analysis were: female gender, being born in Reunion Island, having had a large number of sexual partners in the past year, and being co-infected with another STI. CONCLUSIONS: The prevalence of CT in the screened population is higher in Reunion Island than in mainland France, especially in minors. Prevention campaigns targeting minors should be strengthened.
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Minorias Sexuais e de Gênero , Infecções Sexualmente Transmissíveis , Chlamydia trachomatis , Estudos Transversais , Feminino , Homossexualidade Masculina , Humanos , Masculino , Menores de Idade , Reunião/epidemiologiaRESUMO
BACKGROUND: Despite a scarcity of tuberculosis (TB) cost data, a substantial body of evidence has been accumulating for drug-susceptible TB (DS-TB) treatment. In this study, we review unit costs for DS-TB treatment from a provider´s perspective. We also examine factors driving cost variations and extrapolate unit costs across low- and middle-income countries (LMICs).METHODS: We searched published and grey literature for any empirically collected TB cost estimates. We selected a subgroup of estimates looking at DS-TB treatment. We extracted information on activities and inputs included. We standardised costs into an average per person-month, fitted a multi-level regression model and cross-validated country-level predictions. We then extrapolated estimates for facility-based, directly observed DS-TB treatment across countries.RESULTS: We included 95 cost estimates from 28 studies across 17 countries. Costs predictions were sensitive to characteristics such as delivery mode, whether hospitalisation was included, and inputs accounted for, as well as gross domestic product per capita. Extrapolation results are presented with uncertainty intervals (UIs) for LMICs. Predicted median costs per 6 months of treatment were US$315.30 (95% CI US$222.60-US$417.20) for low-income, US$527.10 (95% CI US$395.70-US$743.70) for lower middle-income and US$896.40 (95% CI US$654.00-US$1214.40) for upper middle-income countries.CONCLUSIONS: Our study provides country-level DS-TB treatment cost estimates suitable for priority setting. These estimates, while not standing as a substitute for local high-quality primary data, can inform global, regional and national exercises.
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Países em Desenvolvimento , Tuberculose , Análise Custo-Benefício , Produto Interno Bruto , Custos de Cuidados de Saúde , Humanos , Pobreza , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologiaRESUMO
Health interventions often depend on a complex system of human and capital infrastructure that is shared with other interventions, in the form of service delivery platforms, such as healthcare facilities, hospitals, or community services. Most forms of health system strengthening seek to improve the efficiency or effectiveness of such delivery platforms. This paper presents a typology of ways in which health system strengthening can improve the economic efficiency of health services. Three types of health system strengthening are identified and modelled: (1) investment in the efficiency of an existing shared platform that generates positive benefits across a range of existing interventions; (2) relaxing a capacity constraint of an existing shared platform that inhibits the optimization of existing interventions; (3) providing an entirely new shared platform that supports a number of existing or new interventions. Theoretical models are illustrated with examples, and illustrate the importance of considering the portfolio of interventions using a platform, and not just piecemeal individual analysis of those interventions. They show how it is possible to extend principles of conventional cost-effectiveness analysis to identify an optimal balance between investing in health system strengthening and expenditure on specific interventions. The models developed in this paper provide a conceptual framework for evaluating the cost-effectiveness of investments in strengthening healthcare systems and, more broadly, shed light on the role that platforms play in promoting the cost-effectiveness of different interventions.
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Análise Custo-Benefício , Atenção à Saúde , Programas Governamentais , Humanos , Modelos TeóricosRESUMO
OBJECTIVES: To assess the perceptions, attitudes, and practices of French junior physicians regarding antibiotic use and resistance, and then to identify the characteristics of junior physicians associated with appropriate practices of antibiotic use. METHOD: European junior physicians received an email invitation to complete a 49 item web questionnaire between September 2015 and January 2016. We present the French data. Multivariate regression models were used to identify the characteristics of junior physicians associated with appropriate prescription practices and with consideration of the antibiotic prescription consequences. RESULTS: The questionnaire was completed by 641 junior physicians: family medicine (37%), other medical specialties (e.g., pediatrics, internal medicine, neurology: 45%), surgical specialties (11%), and anesthesiology-intensive care specialty (7%). Most respondents (93%) declared being aware of the risk of bacterial resistance and 41% acknowledged prescribing antibiotics more often than necessary. Two factors were independently associated with appropriate prescription practices: a high perceived level of education on antibiotic use (OR=1.51; 95% CI [1.01-2.30]) and a medical specialty (OR=1.69; 95% CI [1.16-2.46]). Factors independently associated with taking into account adverse events of antibiotics were a good perceived knowledge of antibiotics (OR=3.71; 95% CI [2.09-6.61]), and a high perceived education level on antibiotics (OR=1.70; 95% CI [1.11-2.58]). CONCLUSION: Our data can help better define interventions targeting junior physicians in antibiotic stewardship programs.
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Antibacterianos/uso terapêutico , Atitude do Pessoal de Saúde , Resistência Microbiana a Medicamentos , Corpo Clínico Hospitalar , Percepção , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Gestão de Antimicrobianos/métodos , Gestão de Antimicrobianos/normas , Gestão de Antimicrobianos/estatística & dados numéricos , Feminino , França/epidemiologia , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Corpo Clínico Hospitalar/psicologia , Corpo Clínico Hospitalar/estatística & dados numéricos , Médicos/psicologia , Médicos/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
As a result of a literature-based expert process, this review provides an overview about the principles of palliative care for people with advanced dementia that are relevant for clinical practice. In particular, the indications, impact and aims of palliative care for advanced dementia are described. Life-prolonging measures and management of symptoms at the end of life are discussed. Furthermore, the overview focuses on the legal basis of decision making.
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Demência , Cuidados Paliativos , Tomada de Decisões , Humanos , Cuidados Paliativos/legislação & jurisprudênciaRESUMO
Time of flight (TOF) and depth of interaction (DOI) capabilities can significantly enhance the quality and uniformity of positron emission tomography (PET) images. Many proposed TOF/DOI PET detectors require complex readout systems using additional photosensors, active cooling, or waveform sampling. This work describes a high performance, low complexity, room temperature TOF/DOI PET module. The module uses multiplexed timing channels to significantly reduce the electronic readout complexity of the PET detector while maintaining excellent timing, energy, and position resolution. DOI was determined using a two layer light sharing scintillation crystal array with a novel binary position sensitive network. A 20 mm effective thickness LYSO crystal array with four 3 mm × 3 mm silicon photomultipliers (SiPM) read out by a single timing channel, one energy channel and two position channels achieved a full width half maximum (FWHM) coincidence time resolution of 180 ± 2 ps with 10 mm of DOI resolution and 11% energy resolution. With sixteen 3 mm × 3 mm SiPMs read out by a single timing channel, one energy channel and four position channels a coincidence time resolution 204 ± 1 ps was achieved with 10 mm of DOI resolution and 15% energy resolution. The methods presented here could significantly simplify the construction of high performance TOF/DOI PET detectors.
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Tomografia por Emissão de Pósitrons/instrumentação , Tomografia por Emissão de Pósitrons/métodos , Radiometria/instrumentação , Silício/química , Algoritmos , Eletrônica , Humanos , Interpretação de Imagem Assistida por ComputadorRESUMO
Multiplexing many SiPMs to a single readout channel is an attractive option to reduce the readout complexity of high performance time of flight (TOF) PET systems. However, the additional dark counts and shaping from each SiPM cause significant baseline fluctuations in the output waveform, degrading timing measurements using a leading edge threshold. This work proposes the use of a simple analog filtering network to reduce the baseline fluctuations in highly multiplexed SiPM readouts. With 16 SiPMs multiplexed, the FWHM coincident timing resolution for single [Formula: see text] mm LYSO crystals was improved from 401 ± 4 ps without filtering to 248 ± 5 ps with filtering. With 4 SiPMs multiplexed, using an array of [Formula: see text] mm LFS crystals the mean time resolution was improved from 436 ± 6 ps to 249 ± 2 ps. Position information was acquired with a novel binary positioning network. All experiments were performed at room temperature with no active temperature regulation. These results show a promising technique for the construction of high performance multiplexed TOF PET readout systems using analog leading edge timing pickoff.
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Amplificadores Eletrônicos , Filtração/instrumentação , Tomografia por Emissão de Pósitrons/instrumentação , Contagem de Cintilação/instrumentação , Silício/química , Tomografia Computadorizada por Raios X/instrumentação , Humanos , Tomografia por Emissão de Pósitrons/métodos , Contagem de Cintilação/métodos , Tomografia Computadorizada por Raios X/métodosRESUMO
Using time of flight (ToF) measurements for positron emission tomography (PET) is an attractive avenue for increasing the signal to noise (SNR) ratio of PET images. However, achieving excellent time resolution required for high SNR gain using silicon photomultipliers (SiPM) requires many resource heavy high bandwidth readout channels. A method of multiplexing many SiPM signals into a single electronic channel would greatly simplify ToF PET systems. However, multiplexing SiPMs degrades time resolution because of added dark counts and signal shaping. In this work the relative contribution of dark counts and signal shaping to timing degradation is simulated and a baseline correction technique to mitigate the effect of multiplexing on the time resolution of analog SiPMs is simulated and experimentally verified. A charge sharing network for multiplexing is proposed and tested. Results show a full width at half maximum (FWHM) coincidence time resolution of [Formula: see text] ps for a single 3 mm × 3 mm × 20 mm LYSO scintillation crystals coupled to an array of sixteen 3 mm × 3 mm SiPMs that are multiplexed to a single timing channel (in addition to 4 position channels). A [Formula: see text] array of 3 mm × 3 mm × 20 mm LFS crystals showed an average FWHM coincidence time resolution of [Formula: see text] ps using the same timing scheme. All experiments were performed at room temperature with no thermal regulation. These results show that excellent time resolution for ToF can be achieved with a highly multiplexed analog SiPM readout.
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Contagem de Cintilação/instrumentação , Eletrônica , Tomografia por Emissão de Pósitrons/métodos , Contagem de Cintilação/métodos , Silício/química , Tomografia Computadorizada por Raios X/métodosRESUMO
The final products obtained by the oxidation of small model peptides containing the thioether function, either methionine or S-methyl cysteine, have been characterized by tandem mass spectrometry and IR Multiple Photon Dissociation (IRMPD) spectroscopy. The modified positions have been clearly identified by the CID-MS(2) fragmentation mass spectra with or without loss of sulfenic acid, as well as by the vibrational signature of the sulfoxide bond at around 1000 cm(-1). The oxidation of the thioether function did not lead to the same products in these model peptides. The sulfoxide and sulfone (to a lesser extent) have been clearly identified as final products of the oxidation of S-methyl-glutathione (GS-Me). Decarboxylation or hydrogen loss are the major oxidation pathways in GS-Me, while they have not been observed in tryptophan-methionine and methionine-tryptophan (Trp-Met and Met-Trp). Interestingly, tryptophan is oxidized in the dipeptide Met-Trp, while that is not the case in the reverse sequence (Trp-Met).
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Dipeptídeos/química , Glutationa/análogos & derivados , Glutationa/química , Oxirredução , Espectrofotometria Infravermelho/métodos , Sulfonas/análise , Sulfóxidos/análise , Espectrometria de Massas em Tandem/métodosRESUMO
BACKGROUND: The FYB gene encodes adhesion and degranulation-promoting adaptor protein (ADAP), a hematopoietic-specific protein involved in platelet activation, cell motility and proliferation, and integrin-mediated cell adhesion. No ADAP-related diseases have been described in humans, but ADAP-deficient mice have mild thrombocytopenia and increased rebleeding from tail wounds. PATIENTS AND METHODS: We studied a previously reported family of five children from two consanguineous sibships of Arab Christian descent affected with a novel autosomal recessive bleeding disorder with small-platelet thrombocytopenia. Homozygosity mapping and exome sequencing were used to identify the genetic lesion causing the disease phenotype on chromosome 5. Bone-marrow morphology and platelet function were analyzed. Platelets were characterized by scanning electron microscopy. RESULTS: We identified a homozygous deleterious nonsense mutation, c.393G>A, in FYB. A reduced percentage of mature megakaryocytes was found in the bone marrow. Patients' platelets showed increased basal expression of P-selectin and PAC-1, and reduced increments of activation markers after stimulation with ADP, as detected by flow cytometry; they also showed reduced pseudopodium formation and the presence of trapped platelets between the fibrin fibers after thrombin addition, as observed on scanning electron microscopy. CONCLUSIONS: This is the first report of a disease caused by an FYB defect in humans, manifested by remarkable small-platelet thrombocytopenia and a significant bleeding tendency. The described phenotype shows ADAP to be important for normal platelet production, morphologic changes, and function. It is suggested that mutation analysis of this gene be included in the diagnosis of inherited thrombocytopenia.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Plaquetas/ultraestrutura , Códon sem Sentido , Hemorragia/genética , Hemostasia/genética , Trombocitopenia/genética , Árabes/genética , Plaquetas/metabolismo , Tamanho Celular , Análise Mutacional de DNA , Fosfatase 2 de Especificidade Dupla/sangue , Exoma , Marcadores Genéticos , Predisposição Genética para Doença , Hemorragia/sangue , Hemorragia/diagnóstico , Hemorragia/etnologia , Heterozigoto , Homozigoto , Humanos , Israel/epidemiologia , Microscopia Eletrônica de Varredura , Selectina-P/sangue , Linhagem , Fenótipo , Testes de Função Plaquetária , Valor Preditivo dos Testes , Fatores de Risco , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/etnologiaRESUMO
The design of combined positron emission tomography/magnetic resonance (PET/MR) systems presents a number of challenges to engineers, as it forces the PET system to acquire data in a space constrained environment that is sensitive to electro-magnetic interference and contains high static, radio frequency and gradient fields. In this work we validate fast timing performance of a PET scintillation detector using a potentially very compact, very low power, and MR compatible readout method in which analog silicon photomultipliers (SiPM) signals are transmitted optically away from the MR bore with little or even no additional readout electronics. This analog 'electro-optial' method could reduce the entire PET readout in the MR bore to two compact, low power components (SiPMs and lasers). Our experiments show fast timing performance from analog electro-optical readout with and without pre-amplification. With 3 mm × 3 mm × 20 mm lutetium-yttrium oxyorthosilicate (LYSO) crystals and Excelitas SiPMs the best two-sided fwhm coincident timing resolution achieved was 220 +/- 3 ps in electrical mode, 230 +/- 2 ps in electro-optical with preamp mode, and 253 +/- 2 ps in electro-optical without preamp mode. Timing measurements were also performed with Hamamatsu SiPMs and 3 mm × 3 mm × 5 mm crystals. In the future the timing degradation seen can be further reduced with lower laser noise or improvements SiPM rise time or gain.
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Amplificadores Eletrônicos , Imageamento por Ressonância Magnética/instrumentação , Imagem Multimodal/instrumentação , Tomografia por Emissão de Pósitrons/instrumentação , Lutécio/química , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Sensibilidade e Especificidade , Silicatos/química , Silício/química , Fatores de TempoRESUMO
Protein oxidation is increasingly recognised as an important modulator of biochemical pathways controlling both physiological and pathological processes. While much attention has focused on cysteine modifications in reversible redox signalling, there is increasing evidence that other protein residues are oxidised in vivo with impact on cellular homeostasis and redox signalling pathways. A notable example is tyrosine, which can undergo a number of oxidative post-translational modifications to form 3-hydroxy-tyrosine, tyrosine crosslinks, 3-nitrotyrosine and halogenated tyrosine, with different effects on cellular functions. Tyrosine oxidation has been studied extensively in vitro, and this has generated detailed information about the molecular mechanisms that may occur in vivo. An important aspect of studying tyrosine oxidation both in vitro and in biological systems is the ability to monitor the formation of oxidised derivatives, which depends on a variety of analytical techniques. While antibody-dependent techniques such as ELISAs are commonly used, these have limitations, and more specific assays based on spectroscopic or spectrometric techniques are required to provide information on the exact residues modified and the nature of the modification. These approaches have helped understanding of the consequences of tyrosine oxidation in biological systems, especially its effects on cell signalling and cell dysfunction, linking to roles in disease. There is mounting evidence that tyrosine oxidation processes are important in vivo and can contribute to cellular pathology.
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Tirosina/metabolismo , Oxirredução , Estresse Oxidativo , Tirosina/química , Tirosina/fisiologiaRESUMO
We are developing a 1 mm resolution small animal positron emission tomography (PET) system using 3D positioning cadmium zinc telluride photon detectors comprising 40 mm × 40 mm × 5 mm crystals metalized with a cross-strip electrode pattern with a 1 mm anode strip pitch. We optimized the electrode pattern design for intrinsic sensitivity and spatial, energy and time resolution performance using a test detector comprising cathode and steering electrode strips of varying dimensions. The study found 3 and 5 mm width cathode strips locate charge-shared photon interactions near cathode strip boundaries with equal precision. 3 mm width cathode strips exhibited large time resolution variability as a function of photon interaction location between the anode and cathode planes (~26 to ~127.5 ns full width at half maximum (FWHM) for 0.5 mm and 4.2 mm depths, respectively). 5 mm width cathode strips by contrast exhibited more stable time resolution for the same interaction locations (~34 to ~83 ns FWHM), provided more linear spatial positioning in the direction orthogonal to the electrode planes, and as much as 68.4% improvement in photon sensitivity over the 3 mm wide cathode strips. The results were understood by analyzing the cathode strips' weighting functions, which indicated a stronger 'small pixel' effect in the 3 mm wide cathode strips. Photon sensitivity and anode energy resolution were seen to improve with decreasing steering electrode bias from 0 to -80 V w.r.t. the anode potential. A slight improvement in energy resolution was seen for wider steering electrode strips (400 versus 100 µm) for charge-shared photon interactions. Although this study successfully focused on electrode pattern features for PET performance, the results are generally applicable to semiconductor photon detectors employing cross-trip electrode patterns.
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Cádmio , Tomografia por Emissão de Pósitrons/instrumentação , Telúrio , Zinco , Animais , Eletrodos , Desenho de Equipamento , Modelos Lineares , Fótons , Fatores de TempoRESUMO
Combining PET with MRI in a single system provides clinicians with complementary molecular and anatomical information. However, existing integrated PET/MRI systems do not have time-of-flight (ToF) PET capabilities. This work describes an MRI-compatible front-end electronic system with ToF capabilities. The approach employs a fast arrival-time pickoff comparator to digitize the timing information, and a laser diode to drive a 10 m fiber-optic cable to optically transmit asynchronous timing information to a photodiode receiver readout system. The FWHM jitter of the comparator and this electo-optical link is 11.5 ps in response to a fast digital pulse. When configured with LYSO scintillation crystals and Hamamatsu MPPC silicon photo-multipliers the comparator and electro-optical link achieved a 511 keV coincidence time resolution of 254.7 ps +/- 8.0 ps FWHM with 3 × 3 × 20 mm(3) crystals and 166.5 +/- 2.5 ps FWHM with 3 × 3 × 5 mm(3) crystals.
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Equipamentos e Provisões Elétricas , Imageamento por Ressonância Magnética/instrumentação , Imagem Multimodal/instrumentação , Fenômenos Ópticos , Tomografia por Emissão de Pósitrons/instrumentação , Fibras Ópticas , Fatores de TempoRESUMO
The adoption of solid-state photodetectors for positron emission tomography (PET) system design and the interest in 3D interaction information from PET detectors has lead to an increasing number of readout channels in PET systems. To handle these additional readout channels, PET readout electronics should be simplified to reduce the power consumption, cost, and size of the electronics for a single channel. Pulse-width modulation (PWM), where detector pulses are converted to digital pulses with width proportional to the detected photon energy, promises to simplify PET readout by converting the signals to digital form at the beginning of the processing chain, and allowing a single time-to-digital converter to perform the data acquisition for many channels rather than routing many analogue channels and digitizing in the back end. Integrator based PWM systems, also known as charge-to-time converters (QTCs), are especially compact, reducing the front-end electronics to an op-amp integrator with a resistor discharge, and a comparator. QTCs, however, have a long dead-time during which dark count noise is integrated, reducing the output signal-to-noise ratio. This work presents a QTC based PWM circuit with a gated integrator that shows performance improvements over existing QTC based PWM. By opening and closing an analogue switch on the input of the integrator, the circuit can be controlled to integrate only the portions of the signal with a high signal-to-noise ratio. It also allows for multiplexing different detectors into the same PWM circuit while avoiding uncorrelated noise propagation between photodetector channels. Four gated integrator PWM circuits were built to readout the spatial channels of two position sensitive solid-state photomultiplier (PS-SSPM). Results show a 4 × 4 array 0.9 mm × 0.9 mm × 15 mm of LYSO crystals being identified on the 5 mm × 5 mm PS-SSPM at room temperature with no degradation for twofold multiplexing. In principle, much larger multiplexing ratios are possible, limited only by count rate issues.
Assuntos
Tomografia por Emissão de Pósitrons/instrumentação , Contagem de Cintilação/instrumentação , SilícioRESUMO
Hypochlorous acid and its acid-base counterpart, hypochlorite ions, produced under inflammatory conditions, may produce chloramides of glycosaminoglycans, these being significant components of the extracellular matrix (ECM). This may occur through the binding of myeloperoxidase directly to the glycosaminoglycans. The N-Cl group in the chloramides is a potential selective target for both reducing and oxidizing radicals, leading possibly to more efficient and damaging fragmentation of these biopolymers relative to the parent glycosaminoglycans. In this study, the fast reaction techniques of pulse radiolysis and nanosecond laser flash photolysis have been used to generate both oxidizing and reducing radicals to react with the chloramides of hyaluronan (HACl) and heparin (HepCl). The strong reducing formate radicals and hydrated electrons were found to react rapidly with both HACl and HepCl with rate constants of 1-1.7 × 10(8) and 0.7-1.2 × 10(8)M(-1)s(-1) for formate radicals and 2.2 × 10(9) and 7.2 × 10(8)M(-1)s(-1) for hydrated electrons, respectively. The spectral characteristics of the products of these reactions were identical and were consistent with initial attack at the N-Cl groups, followed by elimination of chloride ions to produce nitrogen-centered radicals, which rearrange subsequently and rapidly to produce C-2 radicals on the glucosamine moiety, supporting an earlier EPR study by M.D. Rees et al. (J. Am. Chem. Soc.125: 13719-13733; 2003). The oxidizing hydroxyl radicals also reacted rapidly with HACl and HepCl with rate constants of 2.2 × 10(8) and 1.6 × 10(8)M(-1)s(-1), with no evidence from these data for any degree of selective attack on the N-Cl group relative to the N-H groups and other sites of attack. The carbonate anion radicals were much slower with HACl and HepCl than hydroxyl radicals (1.0 × 10(5) and 8.0 × 10(4)M(-1)s(-1), respectively) but significantly faster than with the parent molecules (3.5 × 10(4) and 5.0 × 10(4)M(-1)s(-1), respectively). These findings suggest that these potential in vivo radicals may react in a site-specific manner with the N-Cl group in the glycosaminoglycan chloramides of the ECM, possibly to produce more efficient fragmentation. This is the first study therefore to conclusively demonstrate that reducing radicals react rapidly with glycosaminoglycan chloramides in a site-specific attack at the N-Cl group, probably to produce a 100% efficient biopolymer fragmentation process. Although less reactive, carbonate radicals, which may be produced in vivo via reactions of peroxynitrite with serum levels of carbon dioxide, also appear to react in a highly site-specific manner at the N-Cl group. It is not yet known if such site-specific attacks by this important in vivo species lead to a more efficient fragmentation of the biopolymers than would be expected for attack by the stronger oxidizing species, the hydroxyl radical. It is clear, however, that the N-Cl group formed under inflammatory conditions in the extracellular matrix does present a more likely target for both reactive oxygen species and reducing species than the N-H groups in the parent glycosaminoglycans.
Assuntos
Glicosaminoglicanos/metabolismo , Radical Hidroxila/metabolismo , Ácido Hipocloroso/metabolismo , Inflamação/metabolismo , Oxirredução , Espectroscopia de Ressonância de Spin Eletrônica , Elétrons , Matriz Extracelular/metabolismo , Glicosaminoglicanos/química , Heparina/química , Heparina/metabolismo , Ácido Hialurônico/química , Ácido Hialurônico/metabolismo , Radical Hidroxila/química , Ácido Hipocloroso/química , Inflamação/patologia , Cinética , Radiólise de ImpulsoRESUMO
NADPH-oxidase is an enzyme that represents, when activated, the major source of non-mitochondrial reactive oxygen species. In phagocytes, this production is an indispensable event for the destruction of engulfed pathogens. The functional NADPH-oxidase complex consists of a catalytic membrane flavocytochrome b (Cytb(558)) and four cytosolic proteins p47(phox), p67(phox), Rac and p40(phox). The NADPH-oxidase activity is finely regulated spatially and temporally by cellular signaling events that trigger the translocation of the cytosolic subunits to its membrane partner involving post-translational modifications and activation by second messengers such as arachidonic acid (AA). Arachidonic acid in its natural cis-poly unsaturated form (C20:4) has been described to be an efficient activator of the enzyme in vivo and in vitro. In this work, we examined in a cell-free system whether a change of the natural cis geometry to the trans configuration, which could occur either by diet or be produced by the action of free radicals, may have consequences on the functioning of NADPH-oxidase. We showed the inability of mono-trans AA isomers to activate the NADPH-oxidase complex and demonstrated the inhibitory effect on the cis-AA-induced NADPH oxidase activation. The inhibition is mediated by a direct effect of the mono-trans AA which targets both the membrane fraction containing the cytb(558) and the cytosolic p67(phox). Our results suggest that the loss of the natural geometric feature (cis-AA) induces substantial structural modifications of p67(phox) that prevent its translocation to the complex.
Assuntos
Ácido Araquidônico/química , NADPH Oxidases/antagonistas & inibidores , Fosfoproteínas/fisiologia , Animais , Bovinos , Membrana Celular/metabolismo , Grupo dos Citocromos b/química , Citosol/enzimologia , Citosol/metabolismo , Relação Dose-Resposta a Droga , Ácidos Graxos/química , Modelos Biológicos , NADPH Oxidases/química , Neutrófilos/metabolismo , Fagócitos/enzimologia , Fosfoproteínas/química , Pichia/metabolismo , Ligação Proteica , Conformação Proteica , Proteínas Recombinantes/química , Fatores de Tempo , Triptofano/químicaRESUMO
PURPOSE: Patients with hemoglobinopathies who undergo splenectomy are at risk for invasive infections. The aim of this investigation was to present the clinical spectrum of infections in splenectomized patients. METHODS: The study cohort comprised 54 splenectomized patients with beta-thalassemia (ß-thalassemic) and sickle cell disease. The incidence of serious invasive bacterial infections was recorded. All patients received pneumococcal vaccine and all received oral prophylactic penicillin. RESULTS: A total of 22 episodes of serious bacterial infections were identified in 19 patients among the study cohort of 54 splenectomized patients (35%). The clinical spectrum included sepsis (10 patients), bacteremia (8), liver abscess (1), forearm abscess (1), and urinary tract infection (2). The most frequent pathogens were Escherichia coli (8 cases), Steptococcus pneumoniae (5), and Campylobacter (2). 22 patients with ß thalassemia died during the study period: 6 due to bacterial infection and 18 due to cardiomyopathy. The time elapsed between splenectomy and S. pneumoniae infection was significantly shorter than that between splenectomy and infections caused by other pathogens (18 ± 14 vs. 115 ± 93 months, respectively; p = 0.035). CONCLUSIONS: Splenectomized patients with ß thalassemia and sickle cell disease are predisposed to severe infections, with the majority of these infections being caused by Gram-negative microorganisms. The attending physician(s) should take these findings into consideration when deciding upon an empiric antibiotic treatment for splenectomized patients who present with fever or sepsis.
Assuntos
Anemia Falciforme/complicações , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Esplenectomia/efeitos adversos , Talassemia beta/complicações , Adolescente , Adulto , Antibacterianos/uso terapêutico , Bactérias/classificação , Bactérias/isolamento & purificação , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/mortalidade , Criança , Pré-Escolar , Estudos de Coortes , Seguimentos , Humanos , Incidência , Israel/epidemiologia , Penicilinas/uso terapêutico , Vacinas Pneumocócicas/uso terapêutico , Fatores de RiscoRESUMO
This paper investigates the performance of 1 mm resolution cadmium zinc telluride (CZT) detectors for positron emission tomography (PET) capable of positioning the 3D coordinates of individual 511 keV photon interactions. The detectors comprise 40 mm × 40 mm × 5 mm monolithic CZT crystals that employ a novel cross-strip readout with interspersed steering electrodes to obtain high spatial and energy resolution. The study found a single anode FWHM energy resolution of 3.06 ± 0.39% at 511 keV throughout most of the detector volume. Improved resolution is expected with properly shielded front-end electronics. Measurements made using a collimated beam established the efficacy of the steering electrodes in facilitating enhanced charge collection across anodes, as well as a spatial resolution of 0.44 ± 0.07 mm in the direction orthogonal to the electrode planes. Finally, measurements based on coincidence electronic collimation yielded a point spread function with 0.78 ± 0.10 mm FWHM, demonstrating 1 mm spatial resolution capability transverse to the anodes-as expected from the 1 mm anode pitch. These findings indicate that the CZT-based detector concept has excellent performance and shows great promise for a high-resolution PET system.